Gadd45β and Cancer
There are a number of cellular pathways involved in carcinogenesis and cancer progression including the c-Jun N-terminal kinase JNK pathway. JNKs are responsive to cytokines and stress stimuli such as ultraviolet irradiation, heat shock and osmotic shock. Also activated in the response to cytokines and cellular stress is the NF-κB pathway. The NF-κB pathway can inhibit the JNK pathway by crosstalk mediated by Gadd45β and the JNK kinase, mitogen activated protein-kinase kinase 7 (MKK7/JNKK2). MKK7 activity is inhibited by Gadd45β, a member of the Gadd45 family of inducible factors and a direct transcriptional target of NF-κB. This means that Gadd45β mediates NF-κB suppression of JNK signalling by binding to MKK7 and inhibiting its activity. Papa, et al. 2004, Nature Cell Biology 6(2):1462153.
The use of NF-κB inhibitors has been proposed for use in the treatment of cancer and inflammatory diseases. However, because NF-κB has a number of activities including roles in programmed cell death (PCD), immunity, inflammation and tissue development, it is preferred to inhibit specific functions of NF-κB rather than NF-κB itself. A number of Gadd45β inhibitors have therefore been proposed (see for example PCT patent application PCT/GB2010/001970).
The present invention relates to the measurement of cellular levels of Gadd45β and is based on the discovery that an indication of Gadd45β levels is useful in both diagnosis of, and the provision of prognostic and theranostic information relating to certain cancers. The present invention is especially related to multiple myeloma and to related cancers.
Multiple myeloma (MM), also known as plasma cell myeloma and Kahler's disease, is a cancer of plasma cells. MM is currently incurable, although temporary remissions can be induced by use of steroids, chemotherapy, thalidomide and stem cell transplants. According to the American Cancer Society, there are approximately 45,000 people in the United States living with multiple myeloma with approximately 15,000 new cases being diagnosed each year in the United States. The average survival time from diagnosis is approximately three years. Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma and represents approximately 1% of all cancers and approximately 2% of all cancer deaths. The incidence of multiple myeloma appears to be increasing and there is also some evidence that the age of onset of the disease is falling. There is a clear need for improved provision of diagnostic, prognostic and theranostic information relating to multiple myeloma to assist in its diagnosis, to assist in providing a patient or physician with prognostic information and to assist in the provision of information useful in selecting patients most likely to respond to a specific treatment.
A number of methods have been proposed for use in providing diagnostic and/or prognostic information relating to multiple myeloma. For example, US 2005/0112630 discloses placing multiple myeloma patients into distinct clinical sub-groups depending on differential expression of a group of genes thought to be involved in normal plasma cell differentiation. US 2009/0264306 discloses the use of DNA methylation profiles for providing diagnostic and prognostic information relating to a number of haematological malignancies. US 2010/0144673 discloses the provision of useful information regarding multiple myeloma prognosis based on expression levels of the CKS1B gene. WO 03/068935 discloses novel RNA and protein antigens present on tumour cell surfaces and proposed for use in treatment, diagnosis and prognosis of a number of malignancies including multiple myeloma. WO 2010/040124 proposes the use of the gene GOLPH3 in diagnosing, prognosing and monitoring cancer including multiple myeloma.
WO 2004/016744 discloses the use of Gadd45β expression in diagnosing or predicting susceptibility to liver disease wherein decreased Gadd45β expression correlates with disease or with an increased risk of disease.
Multiple myeloma is typically diagnosed following the detection of M-protein (monoclonal gamma globulin or paraprotein) in serum and/or urine and the detection of clonal plasma cells in the bone marrow by histopathology. See Brit. J. Haematol. (2003) 121:749-757 for a review of the classification of multiple myeloma and other monoclonal gammopathies. The cancerous cells are typically CD138 positive cells and such cells may be detected in the plasma, bone marrow or other tissue (for example, lymph nodes, kidneys, spleen and bone) into which they have infiltrated. Whilst existing methods of diagnosis of multiple myeloma are adequate for many purposes, they do not generally provide reliable prognostic information.
It has been reported (Zenmyo et al. Diagnostic Pathol. (2010:5:69)) that Gadd45β expression falls with cancer progression in chondrosarcoma and also in human hepatocellular sarcoma (Qiu et al. Am. J. Pathol. (2003:162, 1961)).
The present invention is based on the discovery that in respect of cancers of the blood and lymphatic system, Gadd45β expression is indicative of cancer and also poorer prognosis and suitability for treatment with Gadd45β inhibitors.